Gram-negative bacteria possess a structural unit in their cell envelope called the outer membrane. This layer, which is not present in gram-positive bacteria, surrounds the cell wall and provides the organism with a major barrier to mammalian host defenses and to the penetration of antibiotics. The principal structural component of the outer membrane is lipopolysaccharide (LPS) and provides the major barrier function of the outer membrane.
For instance, erythromycin and vancomycin, which are active only at very high concentrations against gram-negative organisms, are about 100-fold more active against mutants with deficiencies in LPS biosynthesis. Mutants with deficiencies in the biosynthesis of certain regions of LPS are also susceptible to the lethal actions of elements of host defenses, such as lysozyme, deoxycholate and complement which are ineffective against normal gram-negative cells.
LPS itself is comprised of structural units that include a KDO oligosaccharide and a glycolipid (Lipid A), both of which have been shown to be essential to the viability of the bacterium. Thus, inhibitors of KDO and/or Lipid A biosynthesis represent targets for the discovery of novel gram-negative antibiotics.